Macrophages are important effector cells in recognition and descruction of neoplastic cells and invasive microorganisms. Little is known about the cellular and biochemical events involved in macrophage activation. Activation is believed to involve a complex sequence of phenotypic changes that are acquired in stepwise fashion, resulting in the development of microbicidal activity followed by what appears to be the ultimate step in activation, expression of tumoricidal capacity. See, for example, Hibbs et al., Science 197:279-282 (1977); Meltzer, Lymphokines 3:319-343 (1981); and Ruco et al., J. Immunol. 121:2035-2042 (1978). The primary mechanism of natural activation of macrophages is believed to be through the action of the lymphokine, Macrophage Activating Factor (MAF), secreted by antigen-stimulated lymphocytes. Many agents of diverse biological origin and unrelated chemical structure including Corynebacterium parvum, endotoxin, muramyl dipeptide and soluble mediator(s) (lymphokines) released from antigen or mitogen-stimulated lymphocytes, have been used alone and in combination to render macrophages tumoricidal both in vitro and in vivo. See, for example, Fidler in Fundamental Mechanisms in Human Cancer Immunology, eds, Saunders et al., (Elsevier/North Holland, Amsterdam), pp. 425-438 (1981); Schultz, Adv. Pharm. Chemotherapy 17:157-192 (1980); and Chirigos et al., Modulation of Cellular Immunity in Cancer by Immune Modifiers (Raven Press, New York) p. 1 (1981). Whether activation by these agents occurs via a common mechanism and whether macrophages activated by different agents express qualitatively or quantitatively similar phenotypic markers such as the appearance or disappearance of cell surface antigens has not been established. Identification of immunological marker(s) whose expression parallels the activated phenotype would be of considerable value for studying the mechanism(s) of activation, for standardizing dose-response relationships between different preparations of the same activator and/or different activators and also for large scale screening for novel macrophage activating agents. It also is of potential value in diagnosis of disease states and in target-specific drug delivery.
The use of monoclonal antibodies to macrophages has been directed toward identifying cell surface antigens whose presence (or absence) correlates closely with a specific stage in monocyte-macrophage differentiation. For example, Ho et al., J. Immunol. 128: 1221-1228 (1982), characterized a mononuclear phagocyte antigen termed Mac-2, the expression of which is elicited only by strong inflammatory stimuli. Ezekowitz et al., J. Exp. Med. 154: 60-76 (1981), report that expression of a macrophage antigen recognized by another monoclonal antibody, F4/80, is significantly diminished in activated macrophages.
Taniyama et al., J. Exp. Med. 156:1286-1291 (1982), and Taniyama et al., J. Immunol. 131:1032-1037 (1983), report production of a monoclonal antibody, AcM.1, specific for pyran-activated or Corynebacterium parvum-activated macrophages but not thioglycollate-elicited or protease peptone-elicited macrophages. Reactivity of AcM.1 against MAF-activated macrophages was not reported.
Kaplan et al., J. Immunol. 120:2080 (1978), report a polyclonal antibody specific for activated macrophages.
Oldham, J. Natl. Cancer Inst. 70:789-796 (1983), discusses use of biological response modifiers, that is, agents which stimulate or otherwise regulate a normal biological response, in treatment of neoplasia, and screens for such modifiers.
Monoclonal antibodies were first reported by Kohler and Milstein, Nature 256:495-497 (1975). Since then, monoclonal antibodies have been the subject of intensive research. Interest in monoclonal antibodies stems from their ability to bind to characteristic antigens, making them useful, for example, in diagnosing disease states and delivering pharmaceutical agents to specic target cells.